Changes in Chromosome Number

In genetics as a whole there are few topics that impinge on human affairs quite so directly as this one. Foremost is the fact that a large
proportion of genetically determined ill health in humans is caused by abnormal chromosomenumbers. Additionally, manipulation of
chromosome number is routinely used by breeders to improve agriculturally important species.
Changes in chromosome number are of two basic types: changes in whole chromosome sets (resulting in a condition of aberrant
euploidy) and changes in parts of chromosome sets (resulting in aneuploidy). These topics are covered next.

Aberrant Euploidy
Organisms with multiples of the basic chromosome set are called euploid. We learned in earlier chapters that familiar eukaryotes such
as plants, animals, and fungi carry in their cells either one chromosome set (haploid) or two sets (diploid). In these species, the haploid
and diploid states are both cases of normal euploidy. Organisms that have more or less than the normal number of sets are aberrant
euploids. Polyploids are individual organisms in which there are more than two chromosome sets. They can be represented by
3n (triploid), 4n (tetraploid), 5n (pentaploid), 6n(hexaploid), and so forth. (Recall that the number of sets is called the ploidy or
ploidy level.) In essentially diploid taxa, an individual organism with only one chromosome set (n) is called a monoploid to
distinguish it from species in which all individuals are normally haploid (also n). Examples of these conditions are shown in Table 8-
1.

Table 8-1Chromosome Constitutions in a Normally Diploid Organism with Three Chromosomes (Labeled A, B, and C) in the
Basic Set

Name Designation Constitution Number of chromosomes

Monoploid n ABC 3
Diploid 2n AABBCC 6
Triploid 3n AAABBBCCC 9
Tetraploid 4n AAAABBBBCCCC 12
Monosomic 2n − 1 ABBCC 5

AABCC 5
AABBC 5
Trisomic 2n + 1 AAABBCC 7
AABBBCC 7
AABBCCC 7

Monoploids
Male bees, wasps, and ants are monoploid. In the normal life cycles of these insects, males develop parthenogenetically from
unfertilized eggs. However, in most species, monoploid individuals are abnormal, arising in natural populations as rare aberrations.
The germ cells of a monoploid cannot proceed through meiosis normally, because the chromosomes have no pairing partners. Thus,
monoploids are characteristically sterile. (Male bees, wasps, and ants bypass meiosis; in these types, gametes are produced
by mitosis.)
Polyploids
In aberrant euploids, there is often a correlation between the number of copies of the chromosome set and the size of the organism and
its component parts. For example, typically a tetraploid organism looks very similar to its diploidcounterpart in its proportions, except
that the tetraploid is bigger as a whole and in its component parts. The higher the ploidy level, the larger the size (Figure 8-1).
In the realm of polyploids, we must distinguish between autopolyploids, which are composed of multiple sets orignating from within
one species, and allo-polyploids, which are composed of sets from two or more different species. Allopolyploids form only between
closely related species; however, the different chromosome sets are only partly homologous (homeologous), not fully homologous, as
they are in autopolyploids.
Autopolyploids
Triploids are usually autopolyploids. They arise spontaneously in nature, and they can be constructed by geneticists from the cross of a
4n (tetraploid) and a 2n (diploid). The 2n and the n gametes unite to form a 3n triploid. Triploids are characteristically sterile. The
problem, like that of monoploids, lies in pairing at meiosis. The molecular mechanisms for synapsis or true pairing dictate that pairing
can take place only between two of the three chromosomes of each type (Figure 8-2). Paired homologs (bivalents) segregate to
opposite poles, but the unpaired homologs (univalents) pass to either pole randomly. This happens for every chromosome threesome,
and the result is meiotic products with chromosome numbers intermediate between the haploid and diploid number; such genomes are
termed aneuploid. Aneuploid gametes generally do not give rise to viable offspring. There are a couple of reasons for this. First of all,
in plants, pollen cells are very sensitive to aneuploidy, and aneuploid pollen grains will generally be inviable. Second, the zygotes that
do result from fertilization by an aneuploid gamete will themselves be aneuploid, and typically these zygotes also are inviable. We
will examine the underlying reason for the inviability of aneuploids when we consider gene balance later in the chapter.

Figure 8-2

Two possibilities for the pairing of three homologous chromosomes before the first
meiotic division in a triploid. Notice that the outcome will be the same in both
cases: one resulting cell will receive two chromosomes and the other will receive
just one. The probability that the latter cell can become a
functional haploid gamete is very small, however, because to do so it would also
have to receive only one of the three homologous chromosomes of every other set
in the organism. Note that each chromosome is really a pair of chromatids.
MESSAGE

Polyploids with odd numbers of chromosome sets are sterile or highly infertile,
because their gametes and offspring are aneuploid.

Autotetraploids arise by the doubling of a 2n complement to 4n. This doubling can occur spontaneously, but it can also be induced
artificially through the application of chemical agents that disrupt microtubule polymerization. This process normally takes place in
the formation of spindle fibers in cells undergoing division. A commonly used agent is colchicine, an alkaloid drug extracted from the
autumn crocus. In colchicine-treated cells, an S phase of the cell cycle occurs, but not chromosome segregation or cell division. As the
treated cell enters telophase, a nuclear membrane forms around the entire doubled set of chromosomes (Figure 8-3). Thus,
treating diploid (2n) cells for one cell cycle leads to tetraploids (4n), with exactly four copies of each type of chromosome. Treatment
for an additional cell cycle produces octaploids (8n), and so forth. This method works in both plant and animal cells, but generally
plants seem to be much more tolerant of polyploidy. Note that all alleles in the genotype are doubled. Therefore, if a diploid cell of
genotype A /a ;B /b is doubled, the resulting autotetraploid will be of genotype A /A /a /a ;B /B /b /b.
Figure 8-3 The use of colchicine to generate a diploid from
a monoploid. Colchicine added to mitotic cells
during metaphase and anaphase disrupts spindle fiber
formation, preventing the migration of chromatids after
the centromere is split. A single cell is created that contains
pairs of identical chromosomes that are homozygous at all
loci.

Because 4 is an even number, autotetraploids can have a regular meiosis, although this is by no means always the case. The crucial
factor is how the four chromosomes of each set pair and segregate. There are several possibilities, as shown in Figure 8-4. In cases
where pairing is by bivalents or quadrivalents, the normal meiotic segregation processes result in diploid gametes, which upon fusion
regenerate the tetraploid state.
Figure 8-4

Meiotic pairing possibilities in tetraploids. (Each chromosome is

really two chromatids.) The four homologous chromosomes may
pair as two bivalents or as a quadrivalent. Both possibilities can
yield functional gametes. However, the four chromosomes may also
pair in a univalent-trivalent combination, yielding nonfunctional
gametes. A specific tetraploid can show one or more of these
pairings.
MESSAGE
Polyploid plants are often larger and have larger component parts than their diploid relatives.

Allopolyploids
An allopolyploid is a plant that is a hybrid of two or more species, with two or more copies of each of the input genomes. The
prototypic allopolyploid was an allotetraploid synthesized by G. Karpechenko in 1928. He wanted to make a fertile hybrid that would
have the leaves of the cabbage (Brassica) and the roots of the radish (Raphanus),because they were the agriculturally important parts
of each plant. Each of these species has 18 chromosomes and they are related closely enough to allow intercrossing. A viable hybrid
progeny individual was produced from seed. However, this hybrid was functionally sterile because the 9 chromosomes from the
cabbage parent were different enough from the radish chromosomes that pairs did not synapse and segregate normally:

Eventually, one part of the hybrid plant produced some seeds. On planting, these seeds
produced fertile individuals with 36 chromosomes. All of these individuals were allopolyploids.
They had apparently been derived from spontaneous, accidental chromosome doubling to
2n1+2n2 in one region of the sterile hybrid, presumably in tissue that eventually became
germinal and underwent meiosis. Thus, in 2n1+2n2 tissue, there is a pairing partner for each
chromosome, and balanced gametes of the type n1+ n2 are produced. These gametes fuse to
give 2n1+2n2allopolyploid progeny, which also are fertile. This kind of allopolyploid is sometimes called an amphidiploid, which
means doubled diploid (Figure 8-5). (Unfortunately for Karpechenko, his amphidiploid had the roots of a cabbage and the leaves of a
radish.)

Figure 8-5

The origin of the amphidiploid (Raphanobrassica) formed from

cabbage (Brassica) and radish (Raphanus). The fertile amphidiploid arose in this case
from spontaneous doubling in the 2n=18 sterile hybrid. Colchicine can be used to
promote doubling. (From A. M. Srb, R. D. Owen, and R. S. Edgar, General
Genetics, 2d ed. Copyright 1965 by W. H. Freeman and Company. After G.
Karpechenko, Z. Indukt. Abst. Vererb. 48, 1928, 27.)
When the allopolyploid was crossed with either parental species, sterile offspring
resulted. The offspring of the crosswith radish were 2n1+2n2, constituted from
an n1+n2 gamete from the allopolyploid and an n1 gamete from the radish.
The n2 chromosomes had no pairing partners, so sterility resulted. Consequently,
Karpechenko had effectively created a new species, with no possibility
of gene exchange with its parents. He called his new type Raphanobrassica.
Treating a sterile hybrid with colchicine greatly increases the chances of doubling the chromosome sets. Therefore amphidiploids can
be synthesized routinely.
In nature, allopolyploidy seems to have been a major force in the speciation of plants. There are many different examples. One
particularly satisfying one is shown by the genus Brassica, as illustrated in Figure 8-6. Here three different parent species have
hybridized in all possible pair combinations to form new amphidiploid species.

Figure 8-6

A species triangle, showing how amphidiploidy has

been important in the production of new species
of Brassica.
A particularly interesting natural allopolyploid is
bread wheat, Triticum aestivum(6n=42). By studying
various wild relatives, geneticists have reconstructed
a probable evolutionary history of bread
wheat. Figure 8-7 shows that bread wheat is
composed of two sets of each of three ancestral
genomes. At meiosis, pairing is always between
homologs within an ancestral genome. Hence, in a
bread wheat meiosis, there are always 21 bivalents.
 MESSAGE

Allopolyploid plants can be synthesized by crossing related

species and doubling the chromosomes of the hybrid.
Agricultural applications
Variation in chromosome number is used in several commerical
applications. Some examples follow.
Monoploids
Diploidy is an inherent nuisance when breeders want to induce
and select new gene mutations that are favorable and to find
new combinations of favorable alleles at different loci. New
recessive mutations cannot be detected unless they are
homozygous. Furthermore, favorable allelic combinations in
heterozygotes can be broken up by meiosis. Monoploids
provide a way around some of these problems. In some plant
species, monoploids can be artificially derived from the
products of meiosis in the plant’s anthers. A cell destined to
become a pollen grain can instead be induced by cold treatment to grow into an embryoid, a small dividing mass of monoploid cells.
The embryoid can be grown on agar to form a monoploid plantlet, which can then be potted in soil and allowed to mature (Figure 8-8).

Figure 8-8 Generating monoploid plants by

tissue culture. Pollen grains (haploid) are treated so
that they will grow and are placed on agar plates
containing certain plant hormones. Under these
conditions, haploid embryoids will grow into
monoploid plantlets. After being moved to
a medium containing different plant hormones, these
plantlets will grow into mature monoploid plants
with roots, stems, leaves, and flowers.

Plant monoploids can be exploited in several ways. In one approach, they are first examined for favorable allelic combinations that
have arisen from heterozygosity either already present in the diploid parent or induced in the parent by mutagens. Hence from a parent
that is A / a ; B / b might come a favorable monoploid combination a ; b. The monoploid can then be subjected
to chromosome doubling, through application of microtubule inhibitors such as colchicine, to produce cells that are homozygous
diploid, a / a ; b / b, and capable of normal reproduction.
Another approach is to treat monoploid cells basically as a population of haploid organisms in a mutagenesis-and-selection
procedure. A population of monoploid cells is isolated, their walls are removed by enzymatic treatment, and they are treated
with mutagen. They are then plated on a medium that selects for some desirable phenotype. This approach has been used to select for
resistance to toxic compounds produced by one of the plant’s parasites, as well as to select for resistance to herbicides being used by
farmers to kill weeds. Resistant plantlets eventually grow into haploid plants, which can then be doubled (by using colchicine) into a
pure-breeding, diploid, resistant type.
These powerful techniques can circumvent the normally slow process of meiosis-based plant breeding. They have been successfully
applied to several important crop plants, such as soybeans and tobacco.

MESSAGE
To create new plant lines, geneticists produce monoploids with favorable genotypes and then double the chromosomes to form
fertile, homozygous diploids.

Autotriploids
The bananas that are widely available commercially are sterile triploids with 11 chromosomes in each set The most obvious
expression of the sterility of bananas is that there are no seeds in the fruit that we eat. Another example of the commercial exploitation
of triploidy in plants is the production of triploid watermelons, which also are seedless, aphenotype favored by some for its
convenience.
Autotetraploids
Many autotetraploid plants have been developed as commercial crops because of their increased size (Figure 8-9). Large fruits and
flowers are particularly favored.

Allopolyploids
Allopolyploids can be used in plant breeding to combine the useful features of parental species into one type. Only one
synthetic amphidiploid has ever been widely used commercially—Triticale, an amphidiploid between wheat (Triticum, and rye
(Secale, Hence, for Triticale, This novel plant combines the high yields of wheat with the ruggedness of rye.

Polyploid animals
Polyploidy is more common in plants than in animals, but there are cases of naturally occurring polyploid animals. Examples are
found in flatworms, leeches, and brine shrimps. In these animals, reproduction is by parthenogenesis, the development of a special
type of unfertilized egg into an embryo, without the need for fertilization. Triploid and tetraploid Drosophila have been synthesized
experimentally. However, examples are not limited to these so-called lower forms. Polyploid amphibians and reptiles are surprisingly
common. They have several modes of reproduction. Polyploid male and female frogs and toads participate in a sexual cycle, whereas
polyploid salamanders and lizards are parthenogenetic. The Salmonidae family of fishes (including salmon and trout) is a familiar
example of a group that appears to have originated through ancestral polyploidy.
The sterility of triploids has been commercially exploited in animals as well as plants. Triploid oysters have been developed, and such
oysters have a commercial advantage over their diploid relatives. The diploids go through a spawning season, when they are
unpalatable, but triploids, because of their sterility, do not spawn and are palatable all year round.

Aneuploidy

Aneuploidy is the second major category of chromosome aberrations in which chromosome number is abnormal. An aneuploid is a
individual organism whose chromosome number differs from the wild type by part of a chromosome set. Generally, the aneuploid
chromosome set differs from wild type by only one chromosome or by a small number of chromosomes. An aneuploid can have a
chromosome number either greater or smaller than that of the wild type. Aneuploid nomenclature (see Table 8-1) is based on the
number of copies of the specific chromosome in the aneuploid state. For example, the aneuploid condition 2n−1 is
called monosomic (meaning “one chromosome”) because there is only one copy of some specific chromosome present instead of
the usual two found in its diploidprogenitor. For autosomes in diploid organisms, the aneuploid 2n+1 is called trisomic,2n−1
is monosomic, and 2n−2 (where the −2 represents homologs) is nullisomic. In haploids, n+1 is di-somic. Special symbolism has to be
used to describe sex-chromosome aneuploids, because we are dealing with two different chromosomes (X and Y) and the
homogametic and heterogametic sexes have different sex-chromosome compositions even in euploid individuals. The symbolism
merely lists the copies of each sex chromosome, such as XXY, XYY, XXX, or XO (the “O” stands for absence of a chromosome and is
included to show that the symbol is not a typographical error).

Nondisjunction

The cause of most aneuploid conditions is nondisjunction in the course of meiosis or mitosis. Disjunction is another word for the
normal segregation of homologous chromosomes or chromatids to opposite poles at meiotic or mitotic divisions. Nondisjunction is a
failure of this process, and two chromosomes or chromatids go to one pole and none to the other. In meiotic nondisjunction, the
chromosomes may fail to disjoin at either the first or the second division (Figure 8-10). Either way, n+1 and n−1 gametes are
produced. If an n−1 gamete is fertilized by an n gamete,
a monosomic (2n−1 zygote is produced. The fusion of an n+1 and an n gamete
yields a trisomic 2n+1

Figure 8-10
The origin of aneuploid gametes by nondisjunction at the first or second
meiotic division.
MESSAGE
Aneuploid organisms are produced mainly by nondisjunction at meiosis.
Nondisjunction occurs spontaneously; it is another example of a chance failure of a basic cellular process. The precise molecular
processes that fail are not known, but, in experimental systems, the frequency of nondisjunction can be increased by interference with
microtubule action. It appears that disjunction is more likely to go awry in meiosis I. This likelihood may not be surprising, because
normal anaphase I disjunction requires that proper homologous associations be maintained during prophase I and metaphase I. In
contrast, proper disjunction at anaphase II or at mitosis requires that the centromere splits properly but does not require nearly as
elaborate a process during prophase and metaphase.
Meiosis I nondisjunction can be viewed as the failure to form or maintain a tetrad until anaphase I. Crossovers are implicit in this
process normally. In most organisms, the amount of crossing-over is sufficient to ensure that all tetrads will have at least one exchange
per meiosis. In Drosophila, many of the nondisjunctional chromosomes in newly arising disomic gametes are nonrecombinant, with
one nondisjunctional homolog carrying the markers of one input chromosome and the other homolog carrying the markers of the other
chromosome. Similar observations have been made in human trisomies. In addition, in several different experimental organisms,
mutations that interfere with recombination have the effect of massively increasing the frequency of meiosis I nondisjunction. This
effect points to an important role of crossing-over in maintaining chromosomal associations in the tetrad; in the absence of these
associations, chromosomes are vulnerable to anaphase I nondisjunction.

MESSAGE
Nondisjunction at meiosis I is more frequent than that at meiosis II, indicating the necessity of crossovers in the maintenance
of the intact tetrad until anaphase I.

Monosomics (2 - 1)
Monosomic chromosome complements are generally deleterious. Monosomics for all human autosomes die in utero.
In humans, a sex-chromosome monosomic complement of 44 +1 X produces a phenotype known as Turner
syndrome (XO). Affected people have a characteristic phenotype: they are sterile females, short in stature, and often have a web of
skin extending between the neck and shoulders (Figure 8-11). Although their intelligence is near normal, some of their specific
cognitive functions are defective. About 1 in 5000 female births show Turner syndrome.

Figure 8-11

Characteristics of Turner syndrome, which results from having a single

X chromosome (XO). (Adapted from F. Vogel and A. G. Motulsky, Human
Genetics. Springer-Verlag, 1982.)
Geneticists have used viable plant monosomics to identify the chromosomes that
carry the loci of newly found recessive mutant alleles. For example, a geneticist may
obtain different monosomic lines, each of which lacks a different chromosome.
Homozygotes for the new mutant allele are crossed with each monosomic line, and
the progeny of each cross are inspected. The mutant phenotype appears only in the
progeny of the parent monosomic for the locus-bearing chromosome and thus
identifies it. The test works because half the gametes of a fertile monosomic will
be n−1 and, when such an n−1 gamete is fertilized by a gamete bearing a
new mutation on the homologous chromosome, the mutation will be hemizygous and
hence will be expressed.

Trisomics (2n + 1)
The trisomic condition also is one of chromosomal imbalance and can result in abnormality or death. However, there are many
examples of viable trisomics. Furthermore, trisomics can be fertile. When cells from some trisomic organisms are observed under the
microscope at the time of meiotic chromosome pairing, the trisomic chromosomes are seen to form an associated group of three,
whereas the other chromosomes form regular pairs. What genetic ratios might we expect for genes on the trisomic chromosome? Let
us consider a gene A that is close to the centromere on that chromosome, and let us assume that the genotype is A / a / a. Furthermore,
if we postulate that the two paired chromosomes pass to opposite poles and that the other chromosome passes randomly to either pole,
then we can predict the three equally frequent segregations shown in Figure 8-12. These segregations result in an overall gametic ratio
of 1A:2A / a:2a:1a / a. This ratio and the one corresponding to a trisomic of genotype A / A / a are observed in practice. If a
trisomic tester set is available then a new mutation can be located to a chromosome by determining which of the testers gives the
special ratio.

Figure 8-12

Genotypes of the meiotic products of an A/a/a trisomic. Three segregations are

equally likely.
There are several examples of viable human trisomics. Several sex-
chromosome trisomics can live to adulthood. (In considering human sex-chromosome
trisomies, recall that mammalian sex is determined by the presence or absence of the
Y chromosome.) Each of these types is found in the frequency range of about 1 in
1000 births of the relevant sex. The combination XXY results in Klinefelter
syndrome, males with lanky builds who are mentally retarded and sterile (Figure 8-
13). Another abnormal combination, XYY, has a controversial history. Attempts have
been made to link the XYY condition with a predisposition toward violence.
This linkage is still hotly debated, although it is now clear that an XYY condition in
no way guarantees such behavior. The XYY males are usually fertile. Their meioses
are of the XY type; the extra Y is not transmitted, and their gametes contain either X or Y, never YY or XY. Triplo-X trisomies
(XXX) are phenotypically normal and fertile females; meiosis is of the XX type, producing eggs bearing only one X.

Figure 8-13

Characteristics of Klinefelter syndrome (XXY). (Adapted from F. Vogel

and A. G. Motulsky, Human Genetics. Springer-Verlag, 1982.)
Of human trisomies, the most familiar type is Down syndrome (Figure 8-
14), occurring at a frequency of about 0.15 percent of all live births. Most
cases of Down syndrome are trisomy 21 caused
by nondisjunction of chromosome 21 in a parent who is chromosomally
normal. In this sporadic type of Down syndrome, there is no family history
of aneuploidy. Some rare types of Down syndrome arise from
translocations (a rearrangement discussed later in the chapter), and, in
these cases, there is recurrence in the pedigree because of the transmission
of the translocation.

Figure 8-14
Characteristics of Down syndrome (trisomy 21). Diagrammatic representation of the syndrome in an infant. (Adapted from F. Vogel
and A. G. Motulsky, Human Genetics. Springer-Verlag, 1982.)
The combined phenotypes that make up Down syndrome include mental retardation (with an IQ in the 20-to-50 range), broad flat face,
eyes with an epicanthic fold, short stature, short hands with a crease across the middle, and a large wrinkled tongue. Females may be
fertile and may produce normal or trisomic progeny, but males do not reproduce. Mean life expectancy is about 17 years, and only 8
percent survive past age 40.
The only other human autosomal trisomics to survive to birth are trisomy
13 (Patau syndrome) and trisomy 18 (Edwards syndrome). Both show
severe physical and mental abnormalities. The phenotypic syndrome of
trisomy 13 includes a harelip, a small malformed head, “rockerbottom”
feet, and a mean life expectancy of 130 days. That of trisomy 18 includes
“faunlike” ears, a small jaw, a narrow pelvis, and rockerbottom feet;
almost all babies with trisomy 18 die within the first few weeks after birth.
All other trisomies die in utero.
Down syndrome is related to maternal age; older mothers run a greatly
elevated risk of having Down-syndrome children (Figure 8-15). For this
reason, fetal chromosome analysis (by amniocentesis or by chorionic villus
sampling) is now recommended for older mothers. A less-pronounced paternal-age effect also has been demonstrated.
Even though the maternal-age effect has been known for many years, the cause of it is still not known. Nonetheless, there are some
interesting biological correlations. It is possible that one aspect of the strong maternal-age effect on nondisjunction is an age-
dependent decrease in the probability of keeping the chromosomal tetrad together during prophase I of meiosis. Meiotic arrest of
oocytes (female meiocytes) in late prophase I is a common phenomenon in many animals. In female humans, all oocytes are arrested
at diplotene before birth. Meiosis continues only upon menstruation, which means that proper chromosome associations in the tetrad
must be maintained for decades. If we speculate that, by accident over time, these associations have an increasing probability of
breaking down, we can envision a mechanism contributing to increased maternal nondisjunction with age. Consistent with this
speculation, most nondisjunction related to the maternal-age effect is due to nondisjunction at anaphase I, not anaphase II.

The concept of gene balance

In considering aberrant euploidy, we noted that an increase in the number of full chromosome sets correlates with increased organism
size but that the general shape and proportions of the organism remain very much the same. In contrast, autosomal aneuploidy
typically alters the shape and proportions in characteristic ways. Plants tend to be somewhat more tolerant of aneuploidy than are
animals. Studies in the jimsonweed, Datura stramonium, provide a classical example of the effects of aneuploidy and polyploidy. In
the jimsonweed, the haploid chromosome number is 12. As is expected, the polyploid jimsonweed is proportioned like the normal
diploids, only larger. In contrast, each of the 12 possible trisomics is disproportionate, but in ways different from one another, as
exemplified by changes in the shape of the seed capsule (see Figure 2-11). The 12 different trisomies lead to 12 different and
characteristic shape changes in the capsule. Indeed, these and other characteristics of the individual trisomies are so reliable that the
phenotypic syndrome can be used to identify plants carrying a particular trisomy. Similarly, the 12 monosomies are themselves
different from one another and from each of the trisomies. In general, a monosomic for a particular chromosome is more severely
abnormal than is the corresponding trisomic.
We see similar trends in aneuploids of animals as well. In the fruit fly, Drosophila, the only autosomal aneuploids that survive to
adulthood are trisomics and monosomics for chromosome 4, which is the smallest Drosophilachromosome, representing from only
about 1 to 2 percent of the genome. Trisomics for chromosome 4 are only very mildly affected and are much less severely abnormal
than are monosomic-4 flys. In humans, no autosomal monosomic survives to birth, whereas three autosomal trisomies survive. As is
true with aneuploid jimsonweed, the three surviving trisomies produce unique phenotypic syndromes, owing to the special effects of
altered dosages of each of these chromosomes.
Why are aneuploids so much more abnormal than polyploids? Why do aneuploids for different chromosomes each have their own
characteristic phenotypic effects? And why are monosomics typically more severely affected than the corresponding trisomics? The
answers seem certain to be a matter of gene balance. In a euploid, the ratio of genes on any one chromosome to genes on other
chromosomes is 1:1 (that is, 100 percent), regardless of whether we are considering a monoploid, diploid, triploid, or tetraploid. In
contrast, in an aneuploid, the ratio of genes on the aneuploid chromosome to genes on the other chromosomes differs from wild
type by 50 percent (50 percent for monosomics; 150 percent for trisomics). Thus, we can see that the aneuploid genes are out of
balance. How does this help us to answer the questions raised?
A key fact is that, in general, the amount of transcript produced by a gene is directly proportional to the number of copies of that gene
in a cell. That is, for a given gene, the rate of transcription is directly related to the number of DNA templates. Thus, the more copies
of that gene, the more transcripts are produced. Because of this gene-dosage relation, segmental aneuploids, in which pieces of
individual chromosomes are trisomic or monosomic, have proved to be very useful in locating the positions of genes encoding various
cellular enzymes. The approach is to look for segments of the genome that change the amount of an enzyme proportionally to the
dosage of that genomic segment. This approach has been exploited extensively in Drosophila, where there has been about a 90 percent
success rate in identifying enzyme-coding genes by this method.
We can infer that normal physiology in a cell depends upon the proper ratio of gene products in the euploid cell. This is the normal
gene balance. If the relative dosage of certain genes changes—for example, owing to the removal of one of the two copies of
a chromosome or a segment thereof—physiological imbalances in cellular pathways can arise.
In some cases, the imbalances of aneuploidy are due to a few “major” genes. Such genes can be viewed as haplo-abnormal or triplo-
abnormal or both and contribute significantly to the aneuploid phenotypic syndrome. For example, the study of persons trisomic for
only part of human chromosome 21 has made it possible to localize determinants specific to Down syndrome to various regions of
chromosome 21, hinting that some aspects of the phenotype might be due to trisomy for single major genes in these chromosomal
regions. In addition to these major gene effects, other aspects of aneuploid syndromes are likely to be due to cumulative effects of
aneuploidy for numerous genes whose products are all out of balance. Undoubtedly, the entire aneuploid phenotype is a synthesis of
the imbalance effects of a few major genes, together with a cumulative imbalance for many minor genes.
However, the gene-balance idea does not tell us why having too few gene products (monosomy) is much worse for an organism than
having too many gene products (trisomy). Along the same lines, in well-studied organisms, there are many more haploabnormal genes
than triplo-abnormal ones. An important factor in explaining the abnormality of monosomics is that any deleterious recessives present
on the autosome will be automatically expressed. This same effect is relevant to deletion mutations (see the next section).
How do we apply the idea of gene balance to cases of sex-chromosome aneuploidy? Gene balance holds for sex chromosomes as well,
but we also have to take into account the special properties of the sex chromosomes. In organisms with X-Y sex determination, the Y
chromosome seems to be a degenerate X chromosome in which there are very few functional genes other than some involved in sex
determination itself or in sperm production or both. On the other hand, the X chromosome contains many genes involved in basic
cellular processes (“housekeeping genes”) that just happen to reside on the chromosome that eventually evolved into the X
chromosome. X-Y sex-determination mechanisms have probably evolved independently from 10 to 20 times in different taxonomic
groups. Thus, there appears to be one sexdetermination mechanism for all mammals, but it is completely different from the
mechanism governing X-Y sex determination in fruit flies.
In a sense, X chromosomes are naturally aneuploid. Females have two of them, whereas males have only one. Nonetheless, it has been
found that the X chromosome’s housekeeping genes are expressed to equal extents per cell in both females and males. How is this
accomplished? The answer depends on the organism. In fruit flies, the male’s X chromosome appears to be hyperactivated, allowing it
to be transcribed at twice the rate as either X chromosome in the female. In mammals, in contrast, the rule is that no matter how many
X chromosomes are present, there is only one transcriptionally active X chromosome in each somatic cell. This dosage
compensation is achieved by random X-chromosome inactivation. (A person with two or more X chromosomes is a mosaic of two
cell types in which one or the other X is active.) Thus, XY and XX individuals produce the same amount of X-chromosome
housekeeping geneproducts. X-chromosome inactivation also explains why triplo-X humans are phenotypically normal, inasmuch as
only one of the three X chromosomes is transcriptionally active in a given cell. Similarly, an XXY male is only moderately affected
because only one of his two X chromosomes is active in each cell.
Why are XXY individuals abnormal at all, given that triplo-X individuals are phenotypically normal? It turns out that a small part of
the X chromosome near one telomere—the pseudoautosomal region—is not inactivated by the mechanism of dosage compensation. In
XXY males, this region is active at twice the level of the pseudoautosomal region in XY males. This level appears to have the
consequence of slightly feminizing the phenotype of XXY males, although exactly which pseudoautosomal genes contribute to this
effect is currently unknown. In XXX females, on the other hand, the pseudoautosomal region is active at only 1.5 times the level that
it is in XX females. This lower level of functional aneuploidy in XXX than that in XXY, plus the fact that the pseudoautosomal genes
appear to lead to feminization, may explain the feminized phenotype of XXY individuals. The severity of XO, Turner syndrome, can
be interpreted as being due to the considerable deleterious effects of monosomy for the pseudoautosomal region of the X. As is usually
observed for aneuploids, monosomy for this segment of the X chromosome produces a more abnormal phenotype than does having an
extra copy of the same region (triplo-X females or XXY males).
Human polyploid zygotes do arise through various kinds of mistakes in cell division. Most die in utero. Occasionally, triploid babies
are born, but none survive. This fact seems to violate the principle discussed earlier in this section—namely, that polyploids are more
normal than aneuploids. The explanation for this violation seems to lie with X-chromosome dosage compensation. Part of the rule for
the single active X seems to be that there is one active X for every two copies of the autosomal chromosome complement. Thus, some
cells in triploid mammals are found to have one active X, whereas others have two. Neither situation is in balance with autosomal
genes. Presumably this functional underactivation of housekeeping genes (in 3n cells with one active X) or functional overactivation
(in 3ncells with two active X’s) leads to substantial functional aneuploidy and the inviability of triploid individuals.

MESSAGE
Aneuploidy is nearly always deleterious because of genetic imbalance—the ratio of genes is different from that in euploids and
this difference interferes with the normal function of the genome.